Roux-en-Y gastric bypass (RYGB) is the gold standard therapy used in the fight against the worsening obesity and type 2 diabetes mellitus (T2DM) epidemics. An impressive observation has been the rapid resolution of T2DM within days of surgery and before any substantial weight loss. In fact many specialists recommend RYGB as a 'cure'for T2DM. Unfortunately 70% of diabetic patients do not qualify for weight loss surgery based on the current surgical guidelines. We have been intrigued by the observation that RYGB leads to a rapid resolution of T2DM, and to help us develop a less invasive approach that can be offered to a wider population, have focused our attention on the impact of this procedure on the intestinal Na+/glucose cotransporter SGLT1. SGLT1 is a major intestinal transporter that is responsible for most luminal sugar absorption, and is overexpressed in T2DM and obesity. Interestingly, luminal exposure to glucose leads to an acute and profound increase in intestinal SGLT1 expression, referred to as Intestinal Sweet Sensing (ISS). Several studies have confirmed a critical role for duodenal isolation to the success of RYGB, by a mechanism not related to malabsorption. We contend that duodenal isolation, by blunting ISS alters the absorptive capacity of the remaining intestine to delay the temporal appearance of nutrients and gut hormones in the circulation. Thus, the post-RYGB metabolic benefits arise because nutrient influx is slowed without being prevented. To develop a less invasive alternative to blunt ISS, we have targeted vagal afferent fibers. We hypothesize that blunting of ISS by selective vagal deafferentation with capsaicin (a naturally occurring pepper derivative) will rapidly improve glucose homeostasis, similar to RYGB, and lead to resolution of T2DM and weight loss. We will test this in the following aims: 1. Characterize the mechanism for ISS and assess its dysregulation in disease. 2. Assess ISS function and vagal signaling after duodenal isolation by vagus-sparing RYGB. 3. Study the long term effects of vagal deafferentation on weight and glucose homeostasis. We believe that selective vagal deafferentation will modulate intestinal SGLT1 expression and function, and could enhance or possibly replace current surgical interventions for weight loss and T2DM. The ability to reproduce the success of RYGB with a lower morbidity profile would provide immense benefit to numerous individuals at risk. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes mellitus are major public health problems, to which novel therapeutic strategies are desperately needed. The goal of this project is to characterize regulation of the intestinal Na+/ glucose transporter SGLT1, and evaluate a novel and less invasive approach that may replicate the success of gastric bypass surgery in resolving obesity and diabetes.